1-((benz(g)-indolyl)-lower-alkyl)-4-substituted-piperazines



United States Patent 3,472,855 1-[(BENZ[g]-]NDOLYL)-LOWER-ALKYL]-4-SUBSTITUTED-PIPERAZINES Sydney Archer, Bethlehem, N .Y., assignor toSterling Drug Inc., New York, N.Y., a corporation of Delaware NoDrawing. Continuation-in-part of application Ser. No.

481,075, Aug. 19, 1965, which is a continuation-in-part of applicationSer. No. 254,475, Jan. 28, 1963. This application May 29, 1967, Ser. No.642,196

Int. Cl. C07d 57/00; A61k 27/00 US. Cl. 260-268 3 Claims ABSTRACT OF THEDISCLOSURE New 1- [benz [g] -indolyl -lower-a1kyl]-4-substituted-piperazines zndzc a+ad to be useful as tranquilizers,sedatives, skeletal muscle relaxants, adrenolytics, hypothermic agents,anti-convulsants, hypotensive, and cardiovascular agents.

Het-Y-N wherein R is hydrogen or a lower-alkyl, hydroxy-loweralkyl,phenyl, phenyl-lower-alkyl, benzhydryl, phenyllower-alkenyl,cycloalkyl-lower-alkyl, or pyridyl radical; Y is lower-alkelene of fromone to six carbon atoms; and Het is a benz[g]-indolyl radical.

In the above general Formula I, when R represents a lower-alkyl radical,it can be straight or branched and can contain from one to about sixcarbon atoms and thus stands, inter alia, for methyl, ethyl, isobutyl,n-hexyl, and

the like.

When R represents an hydroxy-lower-alkyl radical, it can be staright orbranched, can contain from two to six carbon atoms and is such that theoxygen atom of the hydroxy-lower-alkyl group and the nitrogen atom ofthe piperazine ring are separated by at least two carbon atoms. R thusalso stands, inter alia, for Z-hydroxyethyl, 3-hydroxy-l-methylpropyl,6-hydroxyhexyl, and the like.

When R represents cycloalkyl-lower-alkyl, the cycloalkyl moiety containsfrom three to seven ring carbon atoms, while the lower-alkyl moietycontains from one to four carbon atoms. R thus also stands forcyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cycloheptylmethyl, 2-cyclohexylethyl, and the like.

When R represents phenyl, phenyl-lower-alkyl, benzhydryl, orphenyl-lower-alkenyl, the benzene ring of said radicals can beunsubstituted or can bear one or more substituents of low molecularweight and of such nature that they do not interfere with or take partin the reac- 3,472,855 Patented Oct. 14, 1969 tions, to be describedhereinafter, used in the preparation of the compounds. Moreover, thenucleus of the group, Het, can also be further substituted by one ormore of such substituents. Examples of such substituents include halogen(including fluorine, chlorine, bromine, and iodine), lower-alkyl,hydroxy, lower-alkoxy, methylenedioxy, ethylenedioxy,lower-alkylmercapto, lower-alkylsulfinyl, lower-alkylsulfonyl, nitro,lower-alkanoyl, sulfamoyl, trifluoromethyl, and the like. When Rrepresents a phenyl-lower-alkyl radical, the lower-alkyl moiety of saidradical can contain from one to four carbon atoms, and when R representsa phenyl-lower-alkenyl radical, the lower-alkenyl moiety of said radicalcan contain from three to four carbon atoms. Thus R represents, interalia, phenyl, benzyl, phenethyl, 4-phenylbutyl, benzhydryl, or cinnamyl,or such radicals substituted in the benzene ring by one or moresubstituents of the nature described above.

In the above general Formula I, the group Y represents lower-alkylene offrom one to six carbon atoms, can be straight or branched, and when thegroup Y is attached to a nitrogen atom of the heterocyclic group, Het,is such that at least two carbon atoms separate the nitrogen atoms ofthe heterocyclic group and the piperizine ring. The lower-alkylenegroup, Y, thus stands, inter alia, for methylene, 1,2-ethylene,1,3-propylene, 2-methyl-1,4-butylene, l,6-hexylene, and the like. I

The compounds of Formula I can also be substituted on the carbon atomsof the piperazine ring by one or more lower-alkyl radicals eachcontaining from one to four carbon atoms.

The compounds of the present invention can be prepared by one or more ofthe following reactions in which Het, R, and Y have the meanings givenabove, Hal represents a halogen atom, Alk represents a lower-alkylradical, and Y is a single bond or lower-alkylene containing from one tofive carbon atoms.

METHOD A Het-Y-Hal HN N-R I 3 METHOD D VII VI METHOD B Us... L,

VIII

METHOD F Het-Y -ii-OH HN METHOD G In Method A above, a (benz[g]-indolyl)-lower-alkyl halide is reacted with an appropriatel-substituted-piperazine. The reaction is preferably carried out at atemperature between about 50 C. and 150 C. in the presence of anacid-acceptor in an organic solvent, inert under the conditions of thereaction, for example anhydrous ethanol, benzene, Xylene, and the like.The purpose of the acidacceptor is to take up the hydrogen halide whichis split out during the course of the reaction. It is a basic substancewhich forms preferably water-soluble by-products easily separable fromthe main product of the reaction and includes such substances as alkalimetal salts of weak acids, e.g. sodium carbonate, sodium bicarbonate,potassium carbonate, sodium acetate, sodium alkoxides, and the like. Theacid-acceptor can also be in the form of an excess quantity of thel-substituted-piperazine.

Method B is used to prepare the compounds of Formula I where Y is a1,2-ethylene group. The intermediate (benz[g]-indolyl) glyoxalyl halidesof Formula III required as intermediates in Method B are prepared byreacting a benz[g]indole with a glyoxalyl halide preferably at atemperature in the range from about -20 C. to 25 C. in an organicsolvent inert under the conditions of the reaction, for example ether,petroleum ether, dioxane, tetrahydrofuran, and the like, thus affordingthe (benz[g]-indolyl)glyoxalyl halides of Formula III. The intermediatesthus prepared are then reacted with a l-substituted-piperazine to givethe 1-[(benz[g]-indolyl)glyoxalyl]-4-substituted-piperazines of FormulaIV. The reaction is preferably carried out at a temperature betweenabout 5 C. and about 65 C. in the presence of an acid-acceptor in anorganic solvent inert under the conditions of the reaction, such astetrahydrofuran, ether, ethylene dichloride, and the like. The purposeand nature of the acid-acceptor are the same as that described above inthe description of Method A. The l-[benz [g]-indolyl)glyoxalyl]-4-substituted-piperazines thus prepared are reactedwith an alkali metal aluminum hydride preferably at a temperaturebetween about 0 C. and about 65 C.

4. in an organic solvent inert under the conditions of the reaction, forexample ether or tetrahydrofuran. It is preferred to use lithiumaluminum hydride in refluxing tetrahydrofuran.

In Method C above, a (benz[-g]-indolyl)-lower-alkane mixed anhydride ofFormula V is reacted with an appropriate l-substituted-piperazine togive the 1-[(benz[g]- indolyl)-lower-alkanoyl]-4-substituted-piperazinesof Formula VI preferably at a temperature between about 20 C. and about20 C. The latter, on reaction with an alkali metal aluminum hydride asdescribed above in the description of Method B, afford the compounds ofFormula I. The intermediate mixed anhydrides of Formula V used asstarting materials in Method C are prepared by reacting a(benz[g]-indolyl)-lower-alkanoic acid With a loWer-alkyl haloformate.The reaction is preferably carried out in the presence of anacid-acceptor, for example triethylamine, at a temperature between about20 C. and about 20 C. in an organic solvent inert under the conditionsof the reaction such as anhydrous acetone, ether, ethylene dichloride,and the like. Acetone is a preferred solvent. The acid-acceptor, whichtakes up the hydrogen halide split out during the course of thereaction, is preferably a basic substance which forms water-solubleby-products easily separable from the product.

In Method D above, a (benz[g]-indolyl)-lower-alkanoyl halide of FormulaVII is reacted with a l-substitutedpiperazine to give the1-[(benz[g]-indolyl)-lower-alkanoyl]-4-substituted-piperazines ofFormula VI. The reaction is preferably carried out at a temperature inthe range from about 5 C. to 65 C. in the presence of an acid-acceptorin an organic solvent inert under the conditions of the reaction, suchas tetrahydrofuran, ether, ethylene dichloride, and the like. Thepurpose and nature of the acid-acceptor are the same as that describedabove in the description of Method A. The 1-[(benz[g]-indo1yl)-lower-alkanoyl]-4-substituted-piperazines of Formula VI thus preparedare then reduced with an alkali metal aluminum hydride as describedabove in the description of Method C.

The 1 [(benz[g] indolyl) lower-alkanoyl1-4-substituted-piperazines ofFormula VI can also be prepared according to Methods B or F. In MethodE, N,N'-thiony1- diimidazole of Formula VIII is first prepared byreacting imidazole with thionyl chloride. The former is then reactedwith a (benz[g]-indolyl)-lower-alkanoic acid, and the resulting N- (benz[g] -indolyl-lower-alkanoyl) imidazole of Formula IX is reacted with al-substituted piperazine to produce the 1-[(benz[g]-indolyl)-loweralkanoyl]-4-substituted-pipenazines of Formula VI. If desired theN,N'-thionyldiimidazole and theN-(benz[g]-indolyllower-alkanoyl)imidazole intermediates can be isolatedprior to reaction in the next succeeding step, but it is advantageous tocarry out the entire sequence of steps up to the formation of the1-[(benz[g]-indolyl)-lower-alkanoyl]-4-substituted-piperazines ofFormula VI in essentially one operation, that is by reacting eachintermediate without isolation with the next succeeding reactant usingthe same solvent medium for the entire sequence of reactions. Suitablesolvents are organic solvents inert under the conditions of thereactions, for example tetrahydrofuran, diethyl ether, dibutyl ether,and the like. The reactions are preferably conducted at a temperature inthe range from about 10 C. to about 50 C.

Alternatively the 1- [bcnz [g] -indolyl -lower-alkanoyl]4-substituted-piperazines of Formula VI can be prepared according toMethod F. This method requires the direct interaction of aheterocyclyl-loWer-alkanoic acid with a l-substituted-piperazine. Thereaction is preferably conducted by direct fusion of the acid and theamine in the absence of any solvent and at a temperature sufficientlyhigh to expel the water formed in the reaction. For this purpose, atemperature in the range from about C. to 350 C. is suitable.

The l [(benz[g]-indolyl)-lower-alkanoyl]-4-substituted-piperazines ofFormula VI produced in each of Methods E and F are then reduced with analkali metal aluminum hydride to the final products of Formula I asdescribed above in the description of Method C.

Method G is used to prepare compounds of Formula I wherein the alkylenechain, Y, is methylene. The reaction is carried out by reacting abenz[g]-indole with formaldehyde and an appropriatel-substituted-piperazine preferably at a temperature between 50 C. andabout 150 C. The formaldehyde can be in the form of an aqueous solution,Le. 40% formalin solution, or a polymeric form of formaldehyde such asparaformaldehyde or trioxymethylene. When such polymeric forms are used,a molar excess of mineral acid, for example hydrochloric acid, is addedto regenerate the free aldehyde from the polymer. The reaction ispreferably carried out in an organic solvent inert under the conditionsof the reaction, such as ethanol, methanol, or B-methylbutanol.

The novel compounds of the instant invention are the bases of Formula Iand the acid-addition and quaternary ammonium salts of said bases, andsaid acid-addition and quaternary ammonium salts are considered to bethe full equivalents of the free bases. The compounds of the inventionin free base form are converted to the acid-addition salt form byinteraction of the base with an acid. In like manner, the free bases canbe regenerated from the acid-addition salt form in the conventionalmanner, that is, by treating the salts with strong aqueous bases, forexample alkali metal hydroxides, alkali metal carbonates and alkalimetal bicarbonates. The bases thus regenerated can then be interactedWith the same ora different acid to give back the same or a differentacid-addition salt. Thus the novel bases and all of their acid-additionsalts are readily interconvertible.

The quaternary ammonium salts are obtained by the addition of esters ofstrong acids to the free base form of the compounds, said esters havinga molecular weight less than about 200. A preferred class of esterscomprises alkyl, alkenyl, and monocarbocyclic aryl-lower-alkyl es- .tersof strong inorganic acids or organic sulfonic acids, including suchcompounds as methyl chloride, methyl bromide, methyl iodide, ethylbromide, propyl chloride, allyl chloride, allyl bromide, methyl sulfate,methyl benzenesulfonate, methyl p-toluene-sulfonate, benzyl chloride,benzyl bromide, and substituted benzyl halides, such as p-chlorobenzylchloride, p-nitrobenzyl chloride, p-methoxybenzyl chloride,o-chlorobenzyl chloride, and the like.

The quaternary ammonium salts are prepared by mixing the free base andester of a strong acid in an inert solvent. Heating may be used tofacilitate the reaction, although salt formation usually takes placereadily at room temperature. The quaternary ammonium salt separatesdirectly or can be obtained by concentration of the solution,

It is also possible to convert one quaternary ammonium salt to anotherin which the anion is different. If the anion of the original quaternarysalt forms a water-insoluble silver salt the quaternary salt will reactwith Silver oxide in aqueous medium to form the corresponding quaternaryammonium hydroxide, the original anion being removed as a precipitate.The quaternary ammonium hydroxide solution can then be neutralized withany desired salt in which the anion is different from that of theoriginal salt. In this way quaternary ammonium salts in which the anionis derived from a weak acid can be prepared.

It will thus be appreciated that Formula I not only represents thestructural configuration of the bases of my invention but is alsorepresentative of the respective structural entity which is common toall of my respective compounds, whether in the form of the free bases orin the form of the acid-addition salts of the bases. I have \found thatby virtue of this common structural entity, the bases and theiracid-addition salts have inherent pharmacodynamic activity of a type tobe more fully described hereinbelow. This inherent pharmacodynamicactivity can be enjoyed in useful form for pharmaceutical .purposes byemploying the free bases themselves or the -acid-addition salts formedfrom pharmaceutically-acceptable acids, that is acids whose anions areinnocuous to the animal organism in effective doses of the salts so thatbeneficial properties inherent in the common structural entityrepresented by the free bases are not vitiated by side-effectsascribable to the anions.

In utilizing this pharmacodynamic activity of the salts of theinvention, I prefer of course to use pharmaceutically-acceptable salts.Although Water-insolubility, high toxicity, or lack of crystallinecharacter may make some particular salt species unsuitable or lessdesirable for use as such in a given pharmaceutical application, thewater-insoluble or toxic salts can be converted to the correspondingpharmaceutically-acceptable bases by decomposition of the salt withaqueous base as described above, or alternatively they can be convertedto any desired pharmaceutically-acceptable acid-addition salt by doubledecomposition reactions involving the anion, for example by ion-exchangeprocedures.

Moreover, apart from their usefulness in pharmaceutical applications, mysalts are useful as characterizing or identifying derivatives of thefree bases or in isolation or purification procedures. Like all of theacid-addition salts, such characterizing or purification saltderivatives can, if desired, be used to regenerate thepharmaceutically-acceptable free bases by reaction of the salts withaqueous base, or alternatively can be converted to apharmaceutically-acceptable acid-addition salt by, for example,ion-exchange procedures.

It will be appreciated from the foregoing that all of the acid-additionand quaternary ammonium salts of my new bases are useful and valuablecompounds, regardless of considerations of solubility, toxicity,physical form, and the like, and are accordingly within the purview ofthe instant invention.

The novel feature of the compounds of the invention, then resides in theconcept of the bases and cationic forms of the new 1[(benz[g]-indolyl)-lower-alkyl]-4-substituted-piperazines and not in anyparticular acid or quaternary moiety or acid anion associated with thesalt forms of my compounds; rather, the acid or quaternary moieties oranions which can be associated in the salt forms are in themselvesneither novel nor critical and therefore can be any acid anion oracid-like substance capable of salt formation with bases. In'fact inaqueous solutions, the base form or water-soluble acid-addition saltform of the compounds of the invention both possess a common protonatedcation or ammonium ion.

Thus the acid-addition salts discussed above and claimed herein areprepared from any organic acid, inorganic acid (including organic acidshaving an inorganic group therein), or organo-metallic acid, organicmonoand polysulfonic and -sulfinic acids, organic phosphorn'c andphosphinic acids, organic acids of arsenic and antimony, organicheterocyclic carboxylic, sulfonic, and sulfinic acids, acidicion-exchange resins, and inorganic acids of any acid forming element orcombination of elements. In addition, other salt-forming compounds whichare acidic in their chemical properties but which are not generallyconsidered as acids in the same sense as carboxylic or sulfonic acidsare also considered to be among the numerous acids which can be used toprepare acidaddition salts of the compounds of the invention. Thus thereis also comprehended acidic phenolic compounds and acidic compoundshaving activated or acidic hydrogen atoms, as for example, picrolonicacid, or barbituric acid derivatives having an acidic proton. Alsocomprehended as salt forming agents are so-called Lewis acids which lacka pair of electrons in the outer electron shell and react with basiccompounds having an unshared pair of electrons to form salts, forexample boron trifluoride.

Thus appropriate acid-addition salts are those derived from such diverseacids as formic acid, acetic acid, isobutyric acid,alpha-mercaptopropionic acid, malic acid, fumaric acid, succinic acid,succinamic acid, tartaric acid, citric acid, lactic acid, benzoic acid,4-methoxybenzoic acid, phthalic acid, anthranilic acid,l-naphthalenecarboxylic acid, cinnamic acid, cyclohexanecarboxylic acid,mandelic acid, tropic acid, crotonic acid, acetylene dicarboxylic acid,sorbic acid, Z-furancarboxylic acid, cholic acid, pyrenecarboxylic acid,2-pyridinecarboxylic acid, 3-indoleacetic acid, quinic acid, sulfamicacid, methanesulfonic acid, isethionic acid, benzenesulfonic acid,p-toluenesulfonic acid, p-aminophenylarsinic acid, phenylstibnic acid,phenylphosphinous acid, methylphosphonic acid, phenylphosphinic acid,hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid,perchloric acid, nitric acid, sulfuric acid, phosphoric acid,hydrocyanic acid, phosphotungstic acid, molybdic acid, phosphomolybdicacid, pyrophosphoric acid, arsenic acid, picric acid, picrolonic acid,barbituric acid, boron trifiuoride, and the like.

The acid-addition salts are prepared either by dissolving the free basein an aqueous solution containing the appropriate acid and isolating thesalt by evaporating the solution, or by reacting the free base and acidin an organic solvent, in which case the salt separates directly or canbe obtained by concentration of the solution.

Pharmacological evaluation of the compounds of Formula I hasdemonstrated that they possess a variety of depressant actions on theautonomic nervous system, the cardiovascular system, and the skeletalmuscular system. They depress psychomotor activity as evidenced bystudies in mice in standard activity cages; they possess sedativeactivity as shown by the potentiation of sleeping time in mice inducedby ether, thiopental sodium, or hexobarbital sodium. They show skeletalmuscle relaxant activity in mice in the inclined screen test. Whenadministered to rats, they show adrenolytic activity as evidenced byantagonism of the pressor effects of epinephrine; they lower the rectaltemperature in mice; they possess anti-convulsant activity in mice asevidenced by their ability to protect mice frompentylenetetrazol-induced convulsions; they lower the blood pressure inrats; and they show cardiovascular activity in dogs as evidenced by theincrease in heart force. These activities indicate their usefulness astranquilizers, sedatives, skeletal muscle relaxants, adrenolytic agents,hypothermic agents, anti-convulsants, hypotensive agents, andcardiovascular agents.

Thus in sedative activity tests in mice using the hexobarbitalpotentiation test described by Wylie, Proc. Soc. Exptl. Biol. Med. 98,716-718 (1958), 1-[2-(2-methylbenz[g]-3-indolyl)ethyl]-4-phenylpiperazine was found to have an ED of73:17.3 mg./kg. onintraperitoneal administration.

The compounds can be prepared for use by dissolving under sterileconditions a salt form of the compounds in water (or an equivalentamount of a non-toxic acid if the free base is used), or in aphysiologically compatible aqueous medium such as saline, and stored inampoules for intramuscular injection. Alternatively, they can beincorporated in unit dosage form as tablets or capsules for oraladministration or in combination with suitable adjuvants such as calciumcarbonate, starch, lactose, talc, magnesium stearate, gum acacia, andthe like. Still further the compounds can be formulated for oraladministration in aqueous alcohol, glycol, or oil solution or oilwateremulsions in the same manner as conventional medicinal substances areprepared.

The chemical structures of the compounds of theinvention are establishedby their mode of synthesis and are corroborated by the correspondencebetween calculated values for the elements and values found by chemicalanalysis.

The following examples will further illustrate specific embodiments ofthe invention without the latter being limited thereto.

EXAMPLE 1 1 [2 (2 methylbenz[g] 3 indolyl)ethyl] 4 phenylpiperazine [I:Het is benz[g] 3 indolyl; Y is CHZCHZ; R is C H A solution of 9 g.(0.057 mole) of a-naphthylhydrazinc, in ml. of acetone, was heated toboiling on a steam bath, and the solvent was removed by distillation.The residue was dissolved in 50 ml. of acetone and ml. of acetic acidand the mixture heated on a steam bath for one hour. The solvent wasremoved in vacuo, the residue dissolved in 300 ml. of acetic acid, andthe mixture saturated with anhydrous hydrogen chloride. After refluxingfor twelve hours, the solvent was removed in vacuo and the residuepoured into cold water giving a solid which was collected, dried,dissolved in benzene, and chromatographed on a column of alumina. Thefraction melting at 132139 C. was recrystallized from heptane giving 5.5g. of 2-methylbenz[g]-indole, M.P. 132.5l36 C. (uncorr.).

The above 2-methylbenz[g]-indole (5.5 g., 0.03 mole) was dissolved in 75ml. of anhydrous ether, and the solution treated with a solution of 12.0g. (0.095 mole) of oxalyl chloride in 20 ml. of ether while stirring andmaintaining the temperature at 10 C. When addition Was complete, themixture was stirred for thirty minutes and the yellow precipitatecollected, washed with ether and dried, giving 6.5 g. of(2-methylbenz[g]-3-indolyl)glyoxalyl chloride. The latter (6.5 g., 0.03mole) was added as a solid over a period of two minutes to a stirredsolution of 14.5 g. (0.09 mole) of l-phenylpiperazine in 250 ml. oftetrahydrofuran while maintaining the temperature at 5 C. The solutionwas stirred for one hour at 0 C. and for an additional two hours at roomtemperature and then poured into one liter of an ice-water mixture. Thesolid which separated was collected, washed with water, air dried, andrecrystallized from an ethanolacetone mixture giving 6.5 g. of1-[(2-methylbenz[g]- 3 indolyl)glyoxalyl] 4 phenylpiperazine, M.P. 295-298" C. (uncorr.).

Six grams (0.015 mole) of the product were reduced with twelve grams(0.03 mole) of lithium aluminum hydride in 400 ml. of tetrahydrofuran byrefluxing the mixture for twenty-four hours. The excess lithium aluminumhydride was decomposed by careful addition of water, and the mixture wasfiltered from the solid precipitate. Washing the filter withtetrahydrofuran, evaporation of the combined filtrates to dryness, andrecrystallization of the crude product from a benzene-ethanol mixturegave 3.4 g. of 1 [2 (2 methylbenz[g] 3 indolyl)ethyl]-4-phenylpiperazine, M.P. 163.0165.0 C.

1 [2 (2 methylbenz[g] 3 indolyl)ethyl] 4- phenylpiperazine can bereacted with hydriodic acid to form 1 [2 (2 methylbenz[g] 3indolyl)ethyl] 4- phenylpiperazine hydriodide, useful as acharacterizing intermediate.

1 [2 (2 methylbenz[g] 3 indolyl)ethyl] 4- phenylpiperazine, in the formof its hydriodide salt, can be converted to the hydrochloride salt bypassing an aqueous solution of the former over an ion-exchange resinsaturated with chloride ions.

1 [2 (2 methylbenz[g] 3 indolyl)ethyl] 4- phenylpiperazine can beconverted to its hydriodide salt and the latter recrystallized forpurification purposes from an appropriate organic solvent. On suspensionof the hydriodide in dilute aqueous sodium hydroxide, extraction of thesuspension with chloroform, and removal of the chloroform from theextracts, 1-[2-(2-methylbenz- [g]-3-indolyl)ethyl]-4-phenylpiperazinecan be recovered in purified free base form.

9 EXAMPLES 2-24 By reacting benz[g]indole with dimethylamine andformaldehyde, reacting the resulting 3-dimethylaminomethylbenz[g1indolewith sodium cyanide, hydrolyzing the resulting3-cyanomethylbenz[g]indole with concentrated hydrochloric acid, reactingthe resulting (benz[g]- 3-indolyl)acetic acid with isobutylchloroformate in acetone in the presence of triethylamine, reacting theresulting mixed anhydride with an appropriate l-substitutedpiperazineand reducing the resulting 1-['(benz[g]-3-indolyl)acety1] 4 substitutedpiperazine with lithium aluminum hydride using the procedure describedabove in Example 1, there can be obtained the compounds of Formula I inTable 1 below where Y, in each instance,

1s 1,2-ethy1ene.

TABLE 1 Example 1 R Piperazine substituent 2 CH 3 HOCHzCHz 4 4-C1C6H45,". 3"CH306H4 2-CH 4-HOCeH4 7 243113006154 6-011 8 3,4- CHzO 5H3 3-01110. 4-CH SCH4 2-n-C Hn 11 comsoonn a CH(CH 12-.- 4CH S02C5H4 2,2-di-CH13 4CF3C5H4 2,5-di-CH 14 4-N02COH4 2-CH 15... 3 CHQCOCGHA 164-NH2SO2C0H4 17 3,4,5-(CH3O)3O0H2 18.-- 2-C1-4-CH CaH 19 CuHsCHz2,6-di-CH 20 aHCH=CHOHz 3,6-di-GH 21 (CQHQ OH 2,5-di-I1-C3H7 22 2-05H4N23 CuHnCHz 24 C H CH2 EXAMPLE 25 1- [2- (benz [g] -3-indoly1) ethyl]-2,6-dimethylpiperazine [I1 Het is benz[g]-3-indolyl; Y is CH CH R is H]By reducing the 1-[2-(benz[g]-3-indolyl)ethyl]-4-benzyl-2,6-dimethylpiperazine described above in Example 19 withhydrogen over a palladium-on-charcoalcatalyst in an ethanol solvent,there is obtained 1-[2-(benz[g]3- indolyl) -ethyl]-2,6-dimethylpiperazine.

EXAMPLE 26 1- [benz [g] -3-indolyl) methyl] -4-phenylpiperazine [1: Hetis benz[ g]-3-indoly1; Y is CH R is C H By reacting benz[g]indole withformaldehyde and 1- phenylpiperazine in glacial acetic acid, there canbe obtained 1- (benz [g] -3-indo1yl methyl] -4-phenylpiperaz1ne.

EXAMPLES 27-29 By reacting benz[g]indole with formaldehyde anddimethylamine in anhydrous ethanol, converting the resulting3-dimethy1aminomethylbenz[g]indole to the methiodide quarternary salt,reacting the latter with diethyl malonate in the presence of sodiumethoxide, and saponitying the product by heating with dilute sulfuricacid, there is obtained fi-(benz[g]-3-indolyl) propionic acid.

By reducing the latter with lithium aluminum hydrid in tetrahydrofuranusing the manipulative procedure described above in Example 1, reactingthe resulting 2-(benz- [g]-3-indolyl)ethano1 with thionyl chloride inthe presence of pyridine, reacting the resulting2-(benz[g]-3-indolyl)ethyl chloride with sodium cyanide, and hydrolyzingthe resulting 'y-(benz[g]-3-indolyl)butyronitrile with aqueous sodiumhydroxide, there is obtained 'y-(benz[g]- 3-indolyl)butyric acid.

By reducing the latter with lithium aluminum hydride, reacting theresulting 4-(benz[g]-3-indolyl)butanol with thinoyl chloride in thepresence of pyridine, reacting the resulting 4-(benz[g]-3-indolyl)butylchloride with diethyl malonate in the presence of sodium ethoxide, andsaponi tying the product by heating With dilute sulfuric acid, there isobtained w-benz[g]-3-indo1y1)hexanoic acid.

By following the manipulative procedure described above in Examples2-24, substituting for the (benz[g]-3- indolyl)acetic acid used thereinand appropriate (benz- [g1-3-indolyl)-lower-alkanoic acid, prepared asdescribed above, and reducing the resulting 1-[(benz[g]-3-indolyl)-lower-alkanoyl] 4 substituted-piperazine with lithium aluminum hydrideusing the manipulative procedure described above in Example 1, there canbe obtained the compounds of Formula I in Table 2 below, where Het, ineach instance, is benz[g]-3-indolyl, and R is phenyl.

1. A compound of the formula Het-Y-N R wherein Het is benz[g]indoly1; Ris hydrogen or loweralkyl, hydroxy-lower-alky1, phenyl,phenyl-lower-alkyl, benzhydryl, phenyl-lower-alkenyl,cycloakyl-lower-alkyl, or pyridyl; and Y is lower-alkylene of from oneto six carbon atoms.

2. A compound according to claim 1 Wherein R is phenyl.

3. 1 [2 (2 methylbenz[g] 3 indo1yl)ethyl] 4- phenyl-piperazine accordingto claim 1 wherein Het is 2-methylbenz[g]-3-indolyl; and Y is1,2-ethylene.

References Cited UNITED STATES PATENTS 2,800,474 7/1957 Voegtli 260-2683,004,975 10/1961 Grob et al 260-268 X 3,133,930 5/1964 Werner 260-268 X3,142,678 7/1964 Rice et a1. 260-268 X 3,282,942 11/1966 Rice et al.260-268 DONALD G. DAUS, Primary Examiner US. Cl. X.R.

T 733 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3, 7 55 Dated I October 14, 1969 Inventor(s) Sydney Archer It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Column 1, line 16, l-[benz should read l-[(benz line 17 ":nd:ca+ad"should read "indicatedline 2 5, "patent should read --patented--; line&1, alkelene should read --alkylene--; line &9, "staright" should read--straight- Column 3, line 15, that part of the flow diagram showing I Nl' 1 should instead show I K 2 W line 72, l-[benz should read l-[ benzColumn 4, line 66, l-[benz should read 1-[ benz Column 9, line 50,l-[benz should read 1-[ benz Column 10, line 41, "cycloakyl" should read--cyc1oa1ky1--.

v S'G'NED M") SEALED M 2 1910 L. M neither 1!" J Anesling Officevan-1.1m E. sasunm, .m.

Connissioner of Patents

